There is currently an epidemic of lifestyle related health disorders. These include, but are not limited to, high blood pressure, diabetes, dyslipidemia, hyperlipidemia, hypercholesterolemia, insulin resistance, inflammation, vascular disease, heart disease, stroke, overweight, obesity, neuronal and/or cognitive dysfunction, dementia, attention and attention/hyperactivity disorders, mood disorders, muscular damage, muscular deterioration or soreness, athletic compromise, sarcopenia, glucose intolerance and other disorders of glucose metabolism, premature aging, skin deterioration and/or damage either associated with, or not associated with, sun exposure, loss of muscle tone, frailty, and bone loss.
Many of these disorders may be understood by analysis of the forces that shaped the evolution of mankind. This analysis provides insight into the interactions between the current environment and the human genome.
Genetic adaptations proceed on a scale measured in hundreds of thousands of years. In contrast, current environmental and dietary changes occur in a much-accelerated fashion. Our “stone age” genes are a poor match for the demands placed upon them by our current lifestyles. This dys-synchrony is manifestly responsible for the predisposition to, and development of, chronic disease.
Multiple factors form the mechanistic basis for the adverse biological processes responsible for the development of chronic disease and many other health problems. An understanding of these factors is important in the fashioning of a meaningful treatment approach. The multiple biological processes, and the resulting forces exerted by them in an organism, have evolved over millions of years and form the basis for the current intricate biological actions and reactions that occur at the cellular level. Each metabolic pathway consists of many small, carefully orchestrated steps that modulate, and in turn are influenced by, many of the chemical pathways within each cell. The most fundamental cellular processes are involved. Subtle effects are magnified many fold at each step of every pathway until ripples are felt in the far reaches of the cell. A perturbation in a metabolic pathway that produces changes exceeding the normal ranges developed through evolution forces may ultimately derail the delicate chemical balance that forms the basis for cellular homeostasis. When this happens, cells, tissues, organs, and even organisms manifest various disease processes.
The evolutionary history responsible for the current metabolic processes in organisms tells an interesting story. The most fundamental property of all living organisms involves the ability to extract and harness energy from their surroundings. This energy is used to drive thermodynamically unfavorable processes involving the generation of cellular order and complexity. They form the basis for cellular functions. These include growth, repair, and reproduction.
In the evolutionary development of living organisms, apparently the safest and most efficient mechanism for cellular energy transduction involved the directed flow of high-energy electrons down an energy ladder in multiple small steps. Each downward step involved the transfer of an electron from one state to another, slightly lower in energy. This was associated with the release of a packet of energy in a biologically acceptable manner, which could be captured and saved for future use. These processes were present in the earliest formulations of photosynthesis and metabolism. They constituted the earliest design of an electron transport chain (ETC). These processes were in place before oxygenic photosynthesis evolved, thus predating the oxidizing atmosphere that dominates the earth today.
Weak electron acceptors such as hydrogen sulfide, organic acids, and nitrate were initially utilized. This only allowed generation of meager amounts of energy. Nevertheless, when atmospheric oxygen became available in high concentration, it became the preferred electron acceptor because it allowed for much more energy generation from fuel sources and had very distinct survival value. Life's transition to an oxygen-rich atmosphere two billion years ago allowed for the unprecedented generation of cellular energy. This benefit was accompanied by the problems of coping with the corrosive and reactive oxygen molecule. The evolutionary events over the past two billion years provided for the development of a modern compromise between the need for a highly efficient oxidative phophorylation process and the need to safely handle the damaging and aging effects of reactive oxygen species (ROS).
The ETC resides on the inner mitochondrial membrane. High-energy electrons flow down an energy gradient while protons are pumped across the mitochondrial membrane. Adenosine triphosphate (ATP) is generated as the protons are transported back across the mitochondrial membrane into the mitochondrial matrix region. For maximal energy (i.e., ATP) production, efficient coupling must exist between the reentry of the protons and ATP generation. In recent years, it has been demonstrated that a finite cellular-membrane proton-conductance exists that is not coupled with ATP generation. This process has been observed to dissipate 20% to 25% of the basal metabolic rate. This is a surprisingly high level of ETC inefficiency that has been preserved over the eons. Because of its high metabolic cost, it must logically provide an extraordinary benefit for the survival of the cell.
Cells have developed powerful anti-oxidant defenses to protect themselves against damage from reactive oxygen species, ROS, which typically comprise free oxygen radicals. Attention in the field has been devoted exclusively to these anti-oxidants. Their function is to spring into action after a free radical is generated and to inactivate or quench it. Even though prevention rather than cure is a more logical way to decrease oxidative damage, no attention has been paid to processes that are critical in the production or generation of ROS. Evidence that forces regulating ROS-production, rather than ex post facto quenching of free radicals, are important and are related to the production of disease; and aging includes the observation that ROS-production is higher in mitochondria from animals with shorter maximal lifespan.